OPA1 Mediated Fatty Acid β‐Oxidation in Hepatocyte: The Novel Insight for Melatonin Attenuated Apoptosis in Concanavalin A Induced Acute Liver Injury

ABSTRACT Melatonin (MLT) has been reported to attenuate Concanavalin A (Con A)‐induced acute liver injury via the inhibition of immune cells. Whereas the response of hepatocyte to Con A‐caused inflammatory storm and the mechanism of MLT on hepatocyte remain not fully understood. Our RNA‐seq and bioinformatic analyses suggested that OPA1 and fatty acid β‐oxidation might be critical. It was found that MLT ameliorated Con A‐induced acute liver injury, promoted mitochondrial fusion, fatty acid β‐oxidation, modulated metabolic reprogramming and inhibited apoptosis. The overexpression and knockdown of OPA1 by adenovirus proved that these processes were governed by OPA1. With the overexpression plasmid, agonist, inhibitor and SiRNA, we found that MLT promoted OPA1 upregulation to enhance fatty acid β‐oxidation, which inhibited apoptosis. The MLT and OPA1‐promoted fatty acid β‐oxidation enhanced ATP production rather than reduced lipid accumulation. AMPK/FOXO1 was required for MLT and OPA1‐mediated fatty acid β‐oxidation and apoptosis. NOTCH1 was also necessary for this apoptotic process. The results were verified in immune deficiency mice and AML12 cells induced by Con A‐stimulated monocyte supernatant. MLT might control the transcription of OPA1 through MEF2A. TOMM70 was critical for MLT translocation and OPA1 upregulation. In conclusion, the present study demonstrated that MLT attenuated Con A‐induced acute liver injury via the OPA1‐controlled fatty acid β‐oxidation to inhibit apoptosis in hepatocyte.